2-(2-Methyl-5-nitro-1-imidazolyl) ethyl-2-thiopseudoureas

ABSTRACT

This invention relates to 2-(2-methyl-5-nitro-1imidazolyl)ethyl-2-thiopseudoureas of the formula   WHEREIN R3 is hydrogen or lower alkyl containing 1-7 carbon atoms and R1 and R2 are hydrogen, lower alkyl containing 1-7 carbon atoms, or R1 and R2 together are vinylene, nitrovinylene, or trimethylene. The compounds of this invention are prepared by the reaction with 1-(2-chloroethyl)-2-methyl-5-nitroimidazole of thiols or of the pseudothiourea tautomers of thioureas. These compounds are potent anti-protozoal agents.

United States Patent [1 1 Tweit [451 May27, 1975 2-( Z-METHYL-S-NITRO-l-IMIDAZOLYL) ETHYL-Z-THIOPSEUDOUREAS [75] Inventor: Robert C. Tweit, Wilmette, Ill.

[73] Assignee: G. D. Searle & Co., Chicago, Ill.

[22] Filed: Nov. 5, 1973 [21] Appl. No.: 412,604

Related U.S. Application Data [63] Continuation-in-part of Ser. No. 293,069, Sept. 28,

1972, abandoned.

[52] U.S. CI. 260/256.5 R; 260/309 [51] Int. Cl. C07D 49/36; C07D 51/40 [58] Field of Search 260/256.5 R, 309

[56] References Cited UNITED STATES PATENTS 3,557,115 l/l971 Manning 260/256.5 3,578,666 5/1971 Manning 260/256.5

FOREIGN PATENTS OR APPLICATIONS 5,567 11/1967 France 260/309 Primary ExaminerStanley J. Friedman Assistant ExaminerLeonard Schenkman Attorney, Agent, or FirmElliot N. Schubert; John J. McDonnell [57] ABSTRACT This invention relates to 2-(2-methyl-5-nitro-1- imidazolyl)ethyl-Z-thiopseudoureas of the formula )'N CH CH s 18 Claims, No Drawings 1 Z-(Z-METHYL-S-NITRO-l-IMIIDAZOLYL) ETHYL-Z-THIOPSEUDOUREAS R NO wherein R is hydrogen or lower alkyl containing 17 carbon atoms and R and R are hydrogen, lower alkyl containing l-7 carbon atoms or R and R together are vinylene, nitrovinylene, or trimethylene and pharmaceutically acceptable acid addition salts thereof. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, B-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, rnaleic acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid, embonic acid, cyclohexylaminosulphonic acid or 1,5- naphthalene disulphonic acid, for example, can be used for salt formation with compounds of the above formula.

A preferred embodiment of R and R together as vinyl and nitrovinyl and R, as hydrogen or lower alkyl containing 1-7 carbon atoms and the pharmaceutically acceptable acid addition salts thereof is l-methyl-2-[2- (2-methyl-5-nitrol -imidazolyl )ethylthio ]-imidazole and the hydrochloride salt thereof.

A preferred embodiment of R as hydrogen or lower alkyl containing 1-7 carbon atoms and R and R together as trimethylene and the pharmaceutically acceptable acid addition salts thereof is 2-[2-( 2-methyl5- nitro-limidazolyl)ethylthio]-l ,4,5,6-tetrahydropyrimidine and the hydrochloride salt thereof.

A preferred embodiment of R R and R as hydrogen or lower alkyl containing 1-7 carbon atoms and the pharmaceutically acceptable acid addition salt thereof is l-methyl-2-[2-methyl-5-nitro-limidazolyl)ethyl]-2-thiopseudourea and the hydrochloride salt thereof.

The compounds are prepared as shown in Scheme I.

Scheme I 1-(2-Chloroethyl)-2-methyl-5-nitroimidazole is reacted with a cyclic thiol or the tautomeric, pseudothiourea, form of substituted thioureas to form 2-(2- methyl-S-nitro-l-imidazolyl)ethyl-2-pseudothioureas in organic polar solvents. Alcohols, dimethylsulfoxide, and dimethylformamide are suitable solvents. Thus, 1- methylthiourea and 1-(2-chloroethyl)-2-methyl-5- nitroimidazole are heated in 2-propanol for 72 hours to provide l-methyl-2- 2-( 2-methyl-5-nitrol imidazolyl)ethyl]-2-thiopseudourea hydrochloride. The free base is obtained by neutralization of the hydrochloride in aqueous base, followed by extraction of the product with ether. Thus the above mentioned hydrochloride is converted to l-methyl-2-[-(2-methyl-5- nitrol-imidazolyl)ethyl]-2-tliiopseudourea.

The compounds of the present invention are useful in view of their anti-microbial activity. They are especially effective in inhibiting the growth of protozoa.

Evidence of the anti-protozoal utility of the present compounds is obtained from standardized tests designed to determine the capacity of test compounds to inhibit the growth of Trichomonas vaginalis. These tests are carried out in the following manner. A modified Diamond medium is prepared by mixing 1200 parts of trypticase (Baltimore Biological Laboratories), 600 parts of yeast extract (Difco), 300 parts of maitose, 60 parts of L-cysteine hydrochloride, 12 parts of L- ascorbic acid, 48 parts of dibasic potassium phosphate, 48 parts of monobasic potassium phosphate and 54,000 parts of distilled water. The pH is adjusted to 6.8 with 40% sodium hydroxide solution and 30 parts of agar (Baltimore Biological Laboratories) is incorporated. The mixture is boiled for one minute to dissolve the agar and is then sterilized in an autoclave. To volumes of the resultant medium is aseptically added 20 volumes of sterile Dubos medium serum. The resultant 7 medium is inoculated with 1% by volume of a 72 hour culture of Trichomonas vaginalis, whereupon 1 ml. of the inoculated medium is mixed with 10 mg. of test compound. The mixture is incubated anaerobically at 37C. for 48 hours and then examined microscopically for the presence of motile trichomonads. If any are observed, the compound is considered inactive. If no motile trichomonads are observed, 0.1 ml. of the incubated mixture is serially diluted and mixed with quantities of the inoculated medium sufficient to produce concentrations of 1000, 100, and l micrograms of test compound per ml. and the resulting mixtures are incubated anaerobically as before at 37C. for 48 hours and then examined microscopically for the presence of motile trichomonads. Controls are provided by concurrent incubation identical with the foregoing except for the absence of test compound.

The following examples are presented to further illustrate the present invention. They should not be construed as limiting it either in spirit or in scope. In these examples quantities are indicated in parts by weight unless parts by volume are specified, and temperatures are indicated in degrees Centrigrade (C.). The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters.

EXAMPLE 1 NCH - HCl Neutralization with base and extraction with ether provides 1-methyl-2-[2-(2-methyl-5-nitro-1- imidazolyl)ethyl]-2-thiopseudourea.

EXAMPLE 2 5.2 Parts of 1,3-dimethylthiourea and 9.5 parts of 1- (2-chloroethyl)-2-methyl-5-nitroimidazole are dissolved in 50 parts by volume of 2-propanol and heated for 72 hours. The solution is cooled and diluted with 25 parts by volume of acetone and 25 parts by volume of ether, thus effecting crystallization of 1,3-dimethyl- 2[2-(2-methyl-5-nitro-limidazolyl)ethyl]-2-thiopseudourea hydrochloride, melting at 202205. The formula of this compound is N-CH N-cn -cn -s-c H01 Neutrahzation with base and extraction with ether pro vides 1,3-dimethyl-2-[ 2-( 2-methyl-5-nitrol imidazolyl)ethyl]-2-thiopseudourea.

EXAMPLE 3 3.8 Parts of thiourea and 9.5 parts of H2 chloroethyl)-2-methyl-5-nitroimidazole are dissolved in 50 parts by volume of 2-propanol and heated for 84 hours, then are cooled. 2-[2-( 2-Methyl-5-nitro-limidazolyl)ethyl]-2-thiopseudourea hydrochloride separates as a solid, melting at 234236. The formula of this compound is Neutralization with base and extraction with ether provides 2-[2-(2-methyl-5-nitro-l-imidazolyl)ethyl]-2- thiopseudourea.

EXAMPLE 4 66 Parts of 1,3-diethylthiourea and 9.5 parts of 1-(2- chloroethyl)-2-methyl-5-nitroimidazole are dissolved in 50 parts by volume of 2-propanol and heated for 72 hours. The solution is cooled and diluted with 25 parts by volume of acetone and 25 parts by volume of ether, resulting in crystallization of 1,3-diethyl-2-[2-(2- methyl-5-nitro-1-imidazolyl)ethyl]-2-thiopseudourea hydrochloride. The formula of this compound is Neutralization with base and extraction with ether provides l ,3-diethyl-2-[2-(2-methyl-5-nitro-1- imidazolyl )ethyl]-2-thiopseudourea.

EXAMPLE 5 1.2 Parts of 1,4,5,6-tetrahydropyrimidine-2-thiol and 1.8 parts of 1-( 2-chloroethyl)-2-methyl-5- nitroimidazole are dissolved in 30 parts by volume of 2-propanol and 10 parts by volume of methanol. The resulting solution is heated for 24 hours and cooled. The solid which forms is crystallized from acetone. This procedure provides 2-[2-(2-methyl-5-nitro-limidazolyl)ethylthio1-l ,4,5,6-tetrahydropyrimidine hydrochloride, melting at 20821 1. The formula of this compound is Neutralization with base and extraction with ether provides 2-[2-(2-methyl-5-nitro-1-imidazo1y)ethylthio]- 1,4,5 ,o-tetrahydropyrimidine.

EXAMPLE 6 8.6 Parts of l-butyl-l,4,5,6-tetrahydropyrimidine-2- thiol and 9.5 parts of l-( 2-chloroethyl)-2-methyl-5- nitroimidazole are dissolved in 50 parts by volume of 2-propanol and heated for 72 hours. The solution is cooled and diluted with 25 parts by volume by acetone and 25 parts by volume of ether. The resulting solid is l-butyl-2-[2-(2-methyl-5-nitro-limidazolyl)ethylthio]-1,4,5,6-tetrahydropyrimidine hydrochloride, melting at 130-l31. The formula of this compound is Neutralization with base and extraction with ether provides l-butyl-2-[2-(2-methyl-5-nitro-1- imidazolyl) ethylthio]-l ,4,5 ,6-tetrahydropyrimidine.

EXAMPLE 7 3.3 Parts of l-methyl-l,4,5,6-tetrahydropyrimidine- 2-thiol and 5.7 parts of 1-(2-chloroethyl)-2-methyl-5- nitroimidazole are dissolved in 25 parts by volume of 2-propanol and heated for 24 hours. The solution is cooled and diluted with parts by volume of acetone and 10 parts by volume of ether. The resulting solid is l-methyl-2-[2-(2-methyl-5-nitro-limidazoly1)ethylthio]-l ,4,5 ,6-tetrahydropyrimidine hydrochloride, melting at l86188. The formula of this compound is Neutralization with base and extraction with ether provides l-methyl-2-[2-(2-methyl-5-nitro-1- imidazolyl)ethylthio]-1 ,4,5,6-tetrahydropyrimidine.

EXAMPLE 8 3.2 Parts of 2-mercapto-l-methylimidazole and 5.7 parts of 1-(2-ch1oroethyl)-2-methy1-5-nitroimidazole are dissolved in parts by volume of 2-propanol and heated for 24 hours. The solution is cooled and diluted with 10 parts by volume of acetone and 10 parts by volume of ether. The resulting solid is 1-rnethyl-2-[2-(2- methyl-S-nitro-l-imidazo]yl)ethylthio]imidazole hydrochloride, melting at 20l-202.5. The formula of this compound is CH 2 I HCl EXAMPLE 9 1-Methyl-2-[2-(2-methy1-5-nitro-1- imidazolyl)ethylthio] imidazole hydrochloride, 9.6 parts is dissolved in 100 parts of water and neutralized with 1.3 parts of sodium hydroxide. The free base separates as a solid, melting at 1 12.5l 14. It is mixed with 25 parts by volume of concentrated nitric acid and 10 parts of water and heated to for an hour. The solution is diluted with 460 parts of water and partly neutralized with sodium carbonate. The solid which forms is separated by filtration and triturated with methanol to yield' l-methyl-2-[2-(2-methyl-5-nitrol imidazolyl)ethylthio]-5-nitroimidazole,. melting at 209214. The formula of this compound is Treatment with hydrochloric acid provides 1-methyl-2- [2-(2-methyl-5-nitro-1- imidazolyl)ethylthio]-5-nitroimidazole hydrochloride.

What is claimed is: 11. A compound of the formula wherein R is hydrogen or lower alkyl containing l7 carbon atoms and R and R are hydrogen, lower alkyl containing 1-7 carbon atoms, or R and R together are vinylene, nitrovinylene, or trimethylene or the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein R1 and R2 are hydrogen or lower alkyl.

3. The compound of claim 2 which is l-methyl-2-[2- (2-methyl-5-nitro- 1-imidazolyl)ethyl]-2- thiopseudourea.

4. The compound of claim 2 which is l-methyl-2-[2- (2-methyl-5-nitrol -imidazolyl )ethyl -2- thiopseudourea hydrochloride.

5. The compound of claim 2 which is 1,3-dimethyl-2- [2-( Z-methyl-S-nitrol -imidazolyl )ethyl]-2- thiopseudourea.

6. The compound of claim 2 which is l,3-dimethyl-2- [2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-2- thiopseudourea hydrochloride.

7. The compound of claim 2 which is 2-[ 2-( Z-methyl- S-nitro-1-imidazolyl)ethyl]-2-thiopseudourea.

8. The compound of claim 2 which is 2-[2-(2-methyl- S-nitro-1-imidazolyl)ethyl]-2-thiopseudourea hydrochloride.

9. A compound of claim 1 wherein R1 and R2 together are trimethylene.

10. The compound of claim 9 which is 2-[2-(2- methyl-S-nitro-1-imidazolyl)ethylthio]-l ,4,5,6- tetrahydropyrimidine.

11. The compound of claim 9 which is 2-[2-(2- methyl-S-nitro-l-imidazolyl)ethylthio]-1,4,5 ,6-

tetrahydropyrimidine hydrochloride.

12. The compound of claim 9 which is l-butyl-2-[2- (2-methyl-5-nitro-limidazolyl )ethylthio]-l ,4,5,-tetrahydropyrimidine.

13. The compound of claim 9 which is 1-butyl-2-[2- (Z-methyl-S-nitrol -imidazolyl )ethylthio1- l ,4,5 ,6- tetrahydropyrimidine hydrochloride.

14. A compound of claim 1 wherein R1 and R2 together are vinyl or nitrovinyl.

15. The compound of claim 14 which is l-methyl-Z- [2-(2-methyl-5-nitro-limidazolyl )ethylthio]-5-nitroimidazole.

16. The compound of claim 14 which is l-methyl-Z- [2-( 2-methyl-5-nitrolimidazolyl)ethylthio]-5-nitroimidazole hydrochloride.

17. The compound of claim 14 which is l-methyl-Z- [2-( 2-methyl-5-nitrol -imidazolyl )ethylthio limidazole.

18. The compound of claim 14 which is l-methyl-2- [2-( 2-methyl-5-nitrol -imidazolyl )ethylthio limidazole hydrochloride. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein R1 and R2 are hydrogen or lower alkyl.
 3. The compound of claim 2 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea.
 4. The compound of claim 2 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea hydrochloride.
 5. The compound of claim 2 which is 1,3-dimethyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea.
 6. The compound of claim 2 which is 1,3-dimethyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea hydrochloride.
 7. The compound of claim 2 which is 2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea.
 8. The compound of claim 2 which is 2-(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)-2-thiopseudourea hydrochloride.
 9. A compound of claim 1 wherein R1 and R2 together are trimethylene.
 10. The compound of claim 9 which is 2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-1,4,5,6-tetrahydropyrimidine.
 11. The compound of claiM 9 which is 2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-1,4,5,6-tetrahydropyrimidine hydrochloride.
 12. The compound of claim 9 which is 1-butyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-1,4,5,6 -tetrahydropyrimidine.
 13. The compound of claim 9 which is 1-butyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-1,4,5,6 -tetrahydropyrimidine hydrochloride.
 14. A compound of claim 1 wherein R1 and R2 together are vinyl or nitrovinyl.
 15. The compound of claim 14 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-5-nitroimidazole.
 16. The compound of claim 14 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)-5-nitroimidazole hydrochloride.
 17. The compound of claim 14 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)imidazole.
 18. The compound of claim 14 which is 1-methyl-2-(2-(2-methyl-5-nitro-1-imidazolyl)ethylthio)imidazole hydrochloride. 